Essential oils have been used for their bioactivity for quite some time. Some essential oils are currently being used as medicaments. For example the plants mentha piperita or mentha arvensis, are the two primary sources of peppermint oil. Peppermint oil is effective at treating the symptoms of gastrointestinal disorders such as irritable bowel syndrome (IBS). These symptoms can include pain, discomfort, bloating, constipation, and/or diarrhea. Clinical trials have demonstrated significant alleviation of the symptoms associated with IBS through the use of peppermint oil in single unit capsules coated with the cellulose acetate-phthalate enteric polymer or other enteric-coating polymers.
For maximal efficacy in the treatment of IBS and to avoid related complications, peppermint oil should be locally delivered to the intestines, while avoiding the stomach. If peppermint oil is released from its dosage form prior to passing through the pyloric sphincter into the intestines, it can irritate the mucous membranes in the digestive tract. Releasing peppermint oil directly into the stomach can cause heartburn (gastric irritation) and gastro-esophogeal reflux disease. Therefore, since peppermint oil is usually administered orally, it should preferably be prepared with an enteric coating.
Enteric-coated single unit capsules for treating irritable bowel syndrome that contain peppermint oil currently exist. But, even though the enteric coated single unit capsules are meant to delay the release of peppermint oil until after the capsule enters the intestines, this approach to treating IBS has several drawbacks. The drawbacks include premature release of the peppermint oil from the capsule in the stomach, resulting in heartburn. Also, the accidental chewing of the capsule causes the enteric coat to rupture prematurely and release the oil in the stomach. Using current formulations of peppermint oil, significant doses are required to achieve an efficacious concentration of peppermint oil in the body. For example, each of the above referenced capsules contains about 200 mg of peppermint oil and must be taken three times a day, 30-60 minutes prior to a meal. The dose can be increased to two capsules taken three times daily in some situations.
Enteric-coated peppermint oil is typically administered as a single-unit formulation. However, in a single-unit formulation, the amount of peppermint oil absorbed by the intestines can vary from dose to dose for several reasons. First, single-unit enteric capsule formulation can get attached to the esophagus because of the muco-adhesive properties of the enteric coat and therefore not enter the stomach within the desired time frame. The single unit enteric coated capsules, like enteric coated single unit tablets have been shown to not release the active ingredient from the single unit formulation because the single unit's size is too large to pass through the constriction in the stomach's pylorus valve. The enteric coat of the capsule may also prematurely crack or rupture because of the force created by the swelling of the gelatin (or hypromellose) seal coat against the thinner outer enteric coat. Peppermint oil containing capsules have a lower specific gravity than the stomach contents, and tend to float rather than settle and then pass through the pylorus constriction between the stomach and the lower intestines.
Non-disintegrating tablets or capsules given with food may stay in the stomach for long times, 10 to 15 hours, before they are emptied into the small intestine. Small particles, with diameters less than 3 mm, are emptied from the stomach more regularly, regardless of whether they are given with food. The 10 to 15 hours that an enteric coated hard gelatin or hypromellose capsule can get exposure to gastric conditions in a fed state may cause the enteric coat to rupture and the hard gelatin (or hypromellose) seal coat to dissolve, resulting in the peppermint oil being released in the stomach and causing heartburn or gastric irritation.
Even when the single unit enteric coated capsule passes through the pylorus intact in a timely fashion, when it reaches the small intestine the coating dissolves and a bolus of oil is released in the intestine. This dosage dumping, a situation in which the active ingredient is released and gives very high local exposure in a segment of the intestine, is also undesirable because it prevents uniform and steady exposure of peppermint oil in the G.I. lumen. This high local exposure to one section of the G.I. lumen may actually aggravate symptoms of IBS.
Single-unit formulations are also significantly influenced by the quantity of food in the stomach. Gastric emptying rates of single unit doses are erratic and unpredictable. Single-unit enteric-coated tablets or capsules taken with food may stay in the stomach for many hours before being emptied into the small intestine. As a result, single-unit formulations present both inter and intra-subject variability with respect to the bioavailable concentration of active ingredient. According to regulatory guidelines, enteric-coated single-unit capsules can never be bioequivalent with multiple-unit enteric-coated dosage forms. A single-unit enteric preparation containing peppermint oil was disclosed in U.S. Pat. No. 4,687,667, which is hereby incorporated by reference in its entirety except to the extent it may be inconsistent with this application.
The currently available delayed release single unit dosage forms containing enteric-coated peppermint oil have another limitation. They dump their primary active ingredient, L-menthol, when the enteric layer disintegrates. The terminal half life of L-menthol is ˜1.34 hours. Therefore, the systemic exposure of L-menthol is limited to approximately 4 hours, resulting in the need for frequent (usually three times a day) to relieve the symptoms of IBS. The use of a single unit non-disintegrating delayed release dosage form is undesirable due to unpredictable absorption and longer residence time in the stomach.